Across a selection of the available literature, the GALC c.1901T>C (p.Leu634Ser) missense variant, also referred to as p.Leu618Ser, has been identified in 12 individuals affected with Krabbe disease, including in a homozygous state in one individual, in a compound heterozygous state in eight individuals, and in a heterozygous state in three individuals. All affected individuals were of Asian descent and have a variable age of onset of Krabbe disease ranging from late-infantile to adult (Furuya et al. 1997; Satoh et al. 1997; Xu et al. 2006; Hossain et al. 2014; Lim et al. 2016; Yoshimura et al. 2016). The p.Leu634Ser variant was also reported in seven asymptomatic newborns including in five in a homozygous state and in two in a compound heterozygous state (Orsini et al. 2016). In the five asymptomatic homozygous newborns, additional GALC variants were detected in cis with the p.Leu634Ser variant. GALC activity was used to assess risk of developing Krabbe disease, with one infant classified as high-risk, one as low-risk, and three as moderate-risk (Orsini et al. 2016). The p.Leu634Ser variant was absent from 65 controls (Furuya et al. 1997), but is reported at a frequency of 0.01923 in the Japanese population of the 1000 Genomes Project. Expression of the p.Leu634Ser variant in COS-1 cells resulted in an approximately 90% reduction in enzyme activity when compared to wild-type (Furuya et al. 1997; Satoh et al. 1997; Shin et al. 2016). Another study demonstrated lack of secretion of the p.Leu634Ser variant protein in transfected HEK293T cells, and also suggested that presence of the variant reduced trafficking of the GALC protein to lysosomes, although a second study showed localization in lysosomes (Spratley et al. 2016; Shin et al. 2016). Despite the high allele frequency, based on the collective clinical evidence, the p.Leu634Ser variant is classified as likely pathogenic for Krabbe disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: The GALC c.1901T>C (p.Leu634Ser) variant, alternatively also known was L618S, involves the alteration of a highly conserved nucleotide and is located in Glyco_hydro_59 domain of the protein. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 83/120532 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0090487 (78/8620). No homozygotes have been reported in general population. In literature, this variant is widely reported as a mild pathogenic variant that causes later-onset Krabbe disease (KD) and is found in several KD patients in homozygous, compound heterozygous and heterozygous states. The variants frequency is high in Japanese patients; a study has reported its allele frequency at 10.7% (11/102 alleles) in a Japanese patient cohort (Hossain_2013). Available functional assays (enzymatic as well as processing assay) further support the variant as a pathogenic variant with ~10% GALC activity in transfected cells. There is some conflicting functional data on the proper localization of the mutant with Shin_2016 and Lim_2016 reporting proper localization while Spratley_2016 reports improper localization. Taken together, this variant is classified as Pathogenic.

This sequence change replaces leucine with serine at codon 634 of the GALC protein (p.Leu634Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs138577661, ExAC 0.9%). This variant has been reported to be compound heterozygous or homozygous in many individuals affected with Krabbe disease (PMID: 27780934, 27679535, 9272171, 24252386, 26865610, 16607461). This variant is also known as Leu618Ser. ClinVar contains an entry for this variant (Variation ID: 225368). Experimental studies have shown that this missense change impairs enzyme activity in vitro (PMID: 27780934, 9272171, 27126738, 24252386, 27638593). For these reasons, this variant has been classified as Pathogenic.

NM_000153.3(GALC):c.1901T>C(L634S) is classified as pathogenic in the context of Krabbe disease and may be associated with a late-onset form of disease. Sources cited for classification include the following: PMID 29951496, 29966168, 30089515, 27638604, 26865610, 27126738, 24252386, 9272171, 26795590, 27780934 and 27679535. Classification of NM_000153.3(GALC):c.1901T>C(L634S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

The information on this website is not intended for direct
diagnostic use or medical decision-making without review by a
genetics professional. Individuals should not change their
health behavior solely on the basis of information contained on
this website. Neither the University of Utah nor the National
Institutes of Health independently verfies the submitted
information. If you have questions about the information
contained on this website, please see a health care
professional.